Multicellular Complex Tumor Spheroid Response to DNA Repair Inhibitors in Combination with DNA-damaging Drugs.

Autor: Dexheimer TS; Molecular Pharmacology Laboratories, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland., Coussens NP; Molecular Pharmacology Laboratories, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland., Silvers T; Molecular Pharmacology Laboratories, Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland., Wright J; Division of Cancer Treatment and Diagnosis, NCI, Rockville, Maryland., Morris J; Division of Cancer Treatment and Diagnosis, NCI, Rockville, Maryland., Doroshow JH; Division of Cancer Treatment and Diagnosis, NCI, Rockville, Maryland., Teicher BA; Division of Cancer Treatment and Diagnosis, NCI, Rockville, Maryland.
Jazyk: angličtina
Zdroj: Cancer research communications [Cancer Res Commun] 2023 Aug 25; Vol. 3 (8), pp. 1648-1661. Date of Electronic Publication: 2023 Aug 25 (Print Publication: 2023).
DOI: 10.1158/2767-9764.CRC-23-0193
Abstrakt: Multicellular spheroids comprised of malignant cells, endothelial cells, and mesenchymal stem cells served as an in vitro model of human solid tumors to investigate the potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways. The DNA-damaging drugs, topotecan, trabectedin, and temozolomide were combined with varied inhibitors of DNA damage response enzymes including PARP (olaparib or talazoparib), ATM (ataxia telangiectasia mutated; AZD-1390), ATR (ataxia telangiectasia and Rad3-related protein; berzosertib or elimusertib), and DNA-PK (DNA-dependent protein kinase; nedisertib or VX-984). A range of clinically achievable concentrations were tested up to the clinical C max , if known. Mechanistically, the types of DNA damage induced by temozolomide, topotecan, and trabectedin are distinct, which was apparent from the response of spheroids to combinations with various DNA repair inhibitors. Although most combinations resulted in additive cytotoxicity, synergistic activity was observed for temozolomide combined with PARP inhibitors as well as combinations of the ATM inhibitor AZD-1390 with either topotecan or trabectedin. These findings might provide guidance for the selection of anticancer agent combinations worthy of further investigation.
Significance: Clinical efficacy of DNA-damaging anticancer drugs can be influenced by the DNA damage response in tumor cells. The potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways was assessed in multicellular tumor spheroids. Although most combinations demonstrated additive cytotoxicity, synergistic cytotoxicity was observed for several drug combinations.
(© 2023 The Authors; Published by the American Association for Cancer Research.)
Databáze: MEDLINE
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